This research is aimed at developing a fundamentally new concept in surfactant chemistry that has been termed, "molecular amphomorphism". In essence, molecular amphomorphism is the ability of a molecule to interconvert between two different forms in response to changes in microenvironment. The immediate objectives of this research are to synthesize a variety of "umbrella-like" amphiphiles that exhibit amphomorphic properties, and to analyze their effects on the membrane permeation behavior of attached polar agents. The broad, long-term objective of this program is to exploit the concept of molecular amphomorphism from the standpoint of drug delivery; i.e., to create umbrella-like amphiphiles that promote the permeation of polar agents (e.g., peptides and antisense oligonucleotides) across cellular membranes, thereby improving their therapeutic potential. The specific aims of this research are: (i) to synthesize a broad series of "umbrella-like" amphiphiles derived from cholic acid, deoxycholic acid, spermine and spermidine, (ii) to prepare corresponding umbrella- peptide and umbrella-antisense oligonucleotide conjugates, (iii) to characterize the permeability properties of each umbrella-peptide and umbrella-antisense oligonucleotide conjugate with respect to bilayers constructed from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and (iv) to define the effectiveness of molecular umbrellas in promoting the cellular entry of antisense oligonucleotides.